Skip to main content
SpringerLink
Log in

Antioxidant Therapeutic Strategies in CNS Disorders

  • Chapter
Metals and Oxidative Damage in Neurological Disorders

Abstract

A major role of oxygen-radical-induced cellular injury in the pathophysiology of acute central nervous system (CNS) injuries and in the pathogenesis of the chronic neurodegenerative disorders has been increasingly recognized. While proteins, nucleic acids, and carbohydrates are all susceptible to oxygen radical damage, perhaps the most avid targets of oxygen-radical-induced injury are cell membrane lipids, including cholesterol and, in particular, polyunsaturated fatty acids. The process of lipid damage by oxygen radicals is known as lipid peroxidation (LP). Central nervous tissue provides an especially avid environment for the occurrence of LP reactions. One reason for this is the high content of iron found in many brain regions, which varies in parallel with the regional sensitivity to ex vivo LP (Zaleska and Floyd, 1985). Iron participates in both the initiation and propagation of LP (see section 17.2). Additionally, brain and spinal cord membrane phospholipids contain a higher proportion of polyunsaturated fatty acids, such as linoleic acid (18:2) and arachidonic acid (20:4), that are sensitive to LP (White, 1973) in comparison to other tissues.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Althaus, J. S., Andrus, P. K., Williams, C. M., VonVoigtlander, P. F., Cazers, A. R., and Hall, E. D., 1993, The use of salicylate hydroxylation to detect hydroxyl radical generation in ischemic and traumatic brain injury: Reversal by tirilazad mesylate (U-74006F), Molec. Chem. Neuropath. 20:147–162.

    Article  CAS  Google Scholar 

  • Althaus, J. S., Oien, T. T., Fici, G. J., Scherch, H. M., Sethy, V. H., and VonVoigtlander, P. F., 1994, Structure-activity relationships of peroxynitrite scavengers: An approach to nitric oxide neurotoxicity, Res. Comm. Chem. Path. Pharmacol. 83:243–254.

    CAS  Google Scholar 

  • Andrus, P. K., Reck, T. J., and Hall, E. D., 1995, Neuroprotective efficacy of the novel brain-penetrating antioxidant U-101033E in the gerbil forebrain ischemia model, J. Neurotrauma 12:967.

    Google Scholar 

  • Araki, N., Greenberg, J. H., Uematsu, D., Sladky, J. T., and Reivich, M., 1992, Effect of superoxide dismutase on intracellular calcium in stroke, J. Cereb. Blood Flow Metab. 12:43–52.

    Article  PubMed  CAS  Google Scholar 

  • Asano, T., Johshita, H., Koide, T., and Takakura, K., 1984, Amelioration of ischaemic cerebral oedema by a free radical scavenger, AVS:l,2-bis(nicotinamido)-propane. An experimental study using a regional ischaemia model in cats, Neurol. Res. 6:163–168.

    PubMed  CAS  Google Scholar 

  • Asano, T., Matsui, T., and Takuwa, Y., 1991, Lipid peroxidation, protein kinase C and cerebral vasospasm, Crit. Rev. Neurosurg. 1:361–379.

    Google Scholar 

  • Audus, K. L., Guillot, F. L., and Braughler, J. M., 1991, Evidence for 21-aminosteroid association with the hydrophobic domains of brain microvessel endothelial cells, Free Rad. Biol. Med. 11:361–371.

    Article  PubMed  CAS  Google Scholar 

  • Beckman, J. S., 1991, The double-edged role of nitric oxide in brain function and superoxide-mediated injury, J. Devel. Physiol. 15:53–59.

    CAS  Google Scholar 

  • Boisvert, D. P. C., and Schreiber, C., 1992, Interrelationship of excitotoxic and free radical mechanisms, in: Pharmacology of Cerebral Ischemia (J. Krieglstein and H. Oberpichler, eds.), Wassenschaftliche Verlaggesellschaft, Stuttgart, pp. 1–10.

    Google Scholar 

  • Braughler, J. M., and Hall, E. D., 1989, Central nervous system trauma and stroke: I. Biochemical considerations for oxygen radical formation and lipid peroxidation, Free Rad. Biol. Med. 6:289–301.

    Article  PubMed  CAS  Google Scholar 

  • Braughler, J. M., and Pregenzer, J. F., 1989, The 21-aminosteroid inhibitors of lipid peroxidation: Reactions with lipid peroxyl and phenoxyl radicals, Free Rad. Biol. Med. 7:125–130.

    Article  PubMed  CAS  Google Scholar 

  • Braughler, J. M., Pregenzer, J. F., Chase, R. L., Duncan, L. A., Jacobsen, E. J., and McCall, J. M., 1987, Novel 21-aminosteroids as potent inhibitors of iron-dependent lipid peroxidation, J. Biol. Chem. 262:10438–10440.

    PubMed  CAS  Google Scholar 

  • Clemens, J. A., Ho, P. P. K., and Panetta, J. A., 1991, LY178002 reduces rat brain damage after transient global ischemia, Stroke 22:1048–1052.

    Article  PubMed  CAS  Google Scholar 

  • Cohen, G., 1986, Monoamine oxidase, hydrogen peroxide and Parkinson’s disease, Adv. Neurol. 45:119–125.

    Google Scholar 

  • Grammas, P., Liu, G.-J., Wood, K., and Floyd, R. A., 1993, Anoxia/reoxygenation induces hydroxyl free radical formation in brain microvessels, Free Rad. Biol. Med. 14:553–557.

    Article  PubMed  CAS  Google Scholar 

  • Gurney, M. E., Cutting, F. B., Zhai, P., Doble, A., Taylor, C. P., Andrus, P. K., and Hall, E. D., 1996, Antioxidants and inhibitors of glutamatergic transmission have therapeutic benefit in a transgenic model of familial amyotrophic lateral sclerosis, Ann. Neurol. 39:147–157.

    Article  PubMed  CAS  Google Scholar 

  • Hall, E. D., 1992, Neuroprotective pharmacology of methylprednisolone: A review, J. Neurosurg. 76:13–22.

    Article  PubMed  CAS  Google Scholar 

  • Hall, E. D., and Braughler, J. M., 1989, Central nervous system trauma and stroke: II. Physiological and pharmacological evidence for the involvement of oxygen radicals and lipid peroxidation, Free Rad. Biol. Med. 6:303–313.

    Article  PubMed  CAS  Google Scholar 

  • Hall, E. D., and Braughler, J. M., 1993, Free radicals in CNS injury, in: Molecular and Cellular Approaches to the Treatment of Neurological Diseases (S. G. Waxman, ed.), Raven Press, New York, pp. 81–105.

    Google Scholar 

  • Hall, E. D., Pazara, K. E., and Braughler, J. M., 1988, The 21-aminosteroid lipid peroxidation inhibitor U-74006F protects against cerebral ischemia in gerbils, Stroke 19:997–1002.

    Article  PubMed  CAS  Google Scholar 

  • Hall, E. D., Yonkers, P. A., Horan, K. L., and Braughler, J. M., 1989, Correlation between attenuation of posttraumatic spinal cord ischemia and preservation of vitamin E by the 21-aminosteroid U-74006F: Evidence for an in vivo antioxidant action, J. Neurotrauma 6:169–176.

    Article  PubMed  CAS  Google Scholar 

  • Hall, E. D., Pazara, K. E., Braughler, J. M., Linseman, K. L., and Jacobsen, E. J., 1990, Non-steroidal lazaroid U-78517F in models of focal and global cerebral ischemia, Stroke 21(Suppl III):83–87.

    Google Scholar 

  • Hall, E. D., Braughler, J. M., Yonkers, P. A., Smith, S. L., Linseman, K. L., Means, E. D., Scherch, H. M., Jacobsen, E. J., and Lahti, R. A., 1991a, U-78517F: A potent inhibitor of lipid peroxidation with activity in experimental brain injury and ischemia, J. Pharmacol. Exp. Ther. 258:688–694.

    PubMed  CAS  Google Scholar 

  • Hall, E. D., Pazara, K. E., and Braughler, J. M., 1991b, Effects of tirilazad mesylate on post-ischemic brain lipid peroxidation and recovery of extracellular calcium in gerbils, Stroke 22:361–366.

    Article  PubMed  CAS  Google Scholar 

  • Hall, E. D., Yonkers, P. A., Andrus, P. K., Cox, J. W., and Anderson, D. K., 1992, Biochemistry and pharmacology of lipid antioxidants in acute brain and spinal cord injury, J. Neurotrauma 9(Suppl 2):425–442.

    Article  Google Scholar 

  • Hall, E. D., Andrus, P. K., and Yonkers, P. A., 1993, Brain hydroxyl radical generation in acute experimental head injury, J. Neurochem. 60:588–594.

    Article  PubMed  CAS  Google Scholar 

  • Hall, E. D., McCall, J. M., and Means, E. D., 1994, Therapeutic potential of the lazaroids (21-aminosteroids) in CNS trauma, ischemia and subarachnoid hemorrhage, Adv. Pharmacol. 28:221–268.

    Article  PubMed  CAS  Google Scholar 

  • Hall, E. D., Andrus, P. K., Smith, S. L., Oostveen, J. A., Scherch, H. M., Lutzke, B. S., Raub, T. J., Sawada, G. A., Palmer, J. R., Banitt, L. S., Tustin, J. M., Belonga, K. L., Ayer, D. E., and Bundy, G. L., 1995, Neuroprotective efficacy of microvascularly-localized versus brain-penetrating antioxidants, Acta Neurochir. 66(Suppl.):107–113.

    Google Scholar 

  • Halliwell, B., and Gutteridge, J. M. C., 1991, Free Radicals in Biology and Medicine, Oxford University Press, New York, pp. 1–543.

    Google Scholar 

  • Imaizumi, S., Woolworth, V., Fishman, R. A., and Chan, P. H., 1990, Liposome-entrapped superoxide dismutase reduces cerebral infarction in cerebral ischemia in rats, Stroke 21:1312–1317.

    Article  PubMed  CAS  Google Scholar 

  • Jenner, P., Schapira, A. H. V., and Marsden, C. D., 1992, New insights into the cause of Parkinson’s disease, Neurology 42:2241–2250.

    Article  PubMed  CAS  Google Scholar 

  • Kassell, N., Haley, E. C., Apperson-Hansen, C., and Alves, W. M., 1996, A randomized double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: A cooperative study in Europe/Australia/New Zealand, J. Neurosurg. 84:221–228.

    Article  PubMed  CAS  Google Scholar 

  • Kukreja, R. C., Kontos, H. A., Hess, M. L., and Ellis, E. F., 1986, PGH synthase and lipoxygenase generate superoxide in the presence of NADH and NADPH, Circ. Res. 59:612–619.

    Article  PubMed  CAS  Google Scholar 

  • Kumar, K., White, B. C., Krause, G. S., Indrieri, R. J., Evans, A. T., Hoehner, T. J., Garritano, A. M., and Koestner, A., 1988, A quantitative morphological assessment of lidoflazine and deferoxamine therapy in global brain ischemia, Neurol. Res. 10:136–140.

    PubMed  CAS  Google Scholar 

  • Lin, Y, and Phillis, J. W., 1992, Deoxycoformycin and oxypurinol: Protection against focal ischemic brain injury in the rat, Brain Res. 571:272–280.

    Article  PubMed  CAS  Google Scholar 

  • MacDonald, R. L., Weir, B. K. A., Runzer, T. D., Grace, M. G. A., and Poznansky, M. J., 1992, Effect of intrathecal superoxide dismutase and catalase on oxyhemoglobin-induced vasospasm in monkeys, Neurosurgery 30:529–539.

    Article  PubMed  CAS  Google Scholar 

  • Mathews, W. R., Marschke, C. K., Jr., and McKenna, R., 1992, Tirilazad mesylate protects endothelium from damage by reactive oxygen, J. Mol. Cell Cardiology 24(suppl. III):517.

    Google Scholar 

  • McCay, P. B., 1985, Vitamin E: Interactions with free radicals and ascorbate, Ann. Rev. Nutr. 5:323–340.

    Article  CAS  Google Scholar 

  • McCord, J. M., 1985, Oxygen-derived radicals in postischemic tissue injury, New Engl. J. Med. 312:159–163.

    Article  PubMed  CAS  Google Scholar 

  • Monyer, H., Hartley, D. M., and Choi, D. W, 1990, 21-Aminosteroids attenuate excitotoxic neuronal injury in cortical cell cultures, Neuron 5:121–126.

    Article  PubMed  CAS  Google Scholar 

  • Oostveen, J. A., Andrus, P. K., and Hall, E. D., 1995a, Attenuation of retrograde degeneration of nigrostriatal dopamine neurons in the gerbil forebrain ischemia model, J. Neurotrauma 12:967.

    Google Scholar 

  • Oostveen, J. A., Carter, D. B., Dunn, E. J., and Hall, E. D., 1995b, Effects of U-101033E on the expression of amyloid protein precursor, apolipoprotein E, glial fibrillary acidic protein and β-amyloid expression following a bilateral carotid occlusion in the gerbil, Neurosci. Abs. 21:1979.

    Google Scholar 

  • Pahlmark, K., Folbergrova, J., Smith, M.-L., and Siesjo, B. K., 1993, Effects of dimethylthiourea on selective neuronal vulnerability in forebrain ischemia in rats, Stroke 24:731–737.

    Article  PubMed  CAS  Google Scholar 

  • Panter, S. S., Braughler, J. M., and Hall, E. D., 1992, Dextran-coupled deferoxamine improves outcome in a murine model of head injury, J. Neurotrauma 9:47–53.

    Article  PubMed  CAS  Google Scholar 

  • Phillis, J. W., 1989, Oxypurinol attenuates ischemia-induced hippocampal damage in the gerbil, Brain Res. Bull 23:267–470.

    Article  Google Scholar 

  • Phillis, J. W., and Cao, X., 1994, N-t-butyl-α-phenylnitrone (PBN) attenuates focal cortical injury in the rat, Stroke 25:262.

    Google Scholar 

  • Phillis, J. W., and Clough-Helfman, C., 1990, Protection from cerebral ischemic injury in gerbils with the spin trap agent N-tert-butyl-alpha nitrone, Neurosci. Letts. 116:315–319.

    Article  CAS  Google Scholar 

  • Prehn, J. H. M., Karkoutly, C., Nuglisch, J., Peruche, B., and Krieglstein, J., 1992, Dihydrolipoate reduces neuronal injury after cerebral ischemia, J. Cereb. Blood Flow Metab. 12:78–87.

    Article  PubMed  CAS  Google Scholar 

  • Raub, T. J., Barsuhn, C. L., Williams, L. R., Decker, D. E., Sawada, G. A., and Ho, N. F. H., 1993, Use of a biophysical-kinetic model to understand the roles of protein binding and membrane partitioning on passive diffusion of highly lipophilic molecules across cellular barriers, J. Drug Targeting 1:269–286.

    Article  CAS  Google Scholar 

  • Rohn, T. T., Hinds, T. R., and Vincenzi, F. F., 1993, Ion transport ATPases as targets for free radical damage: Protection by an aminosteroid of the Ca2+ pump ATPase and Na+/K+ pump ATPase of human red blood cell membranes, Biochem. Pharmacol. 46:525–534.

    Article  PubMed  CAS  Google Scholar 

  • Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A., Donaldson, D., Goto, J., O’Regan, J. P., Deng, H.-X., Rahmani, Z., Krizus, A., McKenna-Yasek, D., Cayabyab, A., Gaston, S. M., Berger, R., Tanzi, R. E., Halperin, J. J., Herzfeldt, B., Van den Bergh, R., Hung, W.-Y., Bird, R., Deng, G., Mulder, D. W., Smyth, C., Laing, N. G., Soriano, E., Pericak-Vance, M. A., Haines, J., Rouleau, G. A., Gusella, J. S., Horvitz, H. R., and Brown, R. H., 1993, Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis, Nature 362:59–62.

    Article  PubMed  CAS  Google Scholar 

  • Rosenthal, R. E., Chanderbhan, R., Marshall, G., and Fiskum, G., 1992, Prevention of post-ischemic brain lipid conjugated diene production and neurological injury by hydroxyl-ethyl starch-conjugated deferoxamine, Free Rad. Biol. Med. 12:29–33.

    Article  PubMed  CAS  Google Scholar 

  • Sano, K., Asano, T., Tanishima, T., and Sasaki, T, 1980, Lipid peroxidation as a cause of cerebral vasospasm, Neurol. Res. 2:253–272.

    PubMed  CAS  Google Scholar 

  • Siesjo, B. K., Agardh, C.-D., and Bengtsson, F., 1989, Free radicals and brain damage, Cerebrovasc. Brain Metab. Rev. 1:165–211.

    CAS  Google Scholar 

  • Smith, C. D., Carney, J. M., Starke-Reed, P. E., Oliver, C. N., Stadtman, E. R., and Floyd, R. A., 1991, Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer’s disease, Proc. Natl. Acad. Sci. USA 88:10540–10543.

    Article  PubMed  CAS  Google Scholar 

  • Smith, M. A., Richey, P. L., Taneda, S., Kutty, R. K., Sayre, L. M., Monnier, V M., and Perry, G., 1994, Advanced Maillard reaction end products, free radicals, and protein oxidation in Alzheimer’s disease, Ann. N.Y. Acad. Sci. 738:447–454.

    Article  PubMed  CAS  Google Scholar 

  • Spina, M. B., and Cohen, G., 1989, Dopamine turnover and glutathione oxidation: Implications for Parkinson’s disease, Proc. Natl. Acad. Sci. USA 86:1398–1400.

    Article  PubMed  CAS  Google Scholar 

  • Subbarao, K. V., Richardson, J. S., and Ang, L. C., 1990, Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro, J. Neurochem. 55:342–345.

    Article  PubMed  CAS  Google Scholar 

  • Traystman, R. J., Kirsch, J. R., and Koehler, R. C., 1991, Oxygen radical mechanisms of brain injury following ischemia and reperfusion, J. Appl. Physiol. 71:1185–1195.

    PubMed  CAS  Google Scholar 

  • Uyama, O., Shiratsuki, N., Matsuyama, T., Nakanishi, T., Matsumoto, Y., Yamada, T., Narita, M., and Sugita, M., 1990, Protective effects of superoxide dismutase on acute cerebral injury of gerbil brain, Free Rad. Biol. Med. 8:265–268.

    Article  PubMed  CAS  Google Scholar 

  • Uyama, O., Matsuyama, T., Michishita, H., Nakamura, H., and Sugita, M., 1992, Protective effects of human recombinant superoxide dismutase on transient ischemic injury of CA1 neurons in gerbils, Stroke 23:75–81.

    Article  PubMed  CAS  Google Scholar 

  • Vollmer, D. G., Hongo, K., Ogawa, H., Tsukahara, T., and Kassell, N. F., 1991, A study of the effectiveness of the iron-chelating agent deferoxamine as vasospasm propylaxis in a rabbit model of subarachnoid hemorrhage, Neurosurgery 28:27–32.

    Article  PubMed  CAS  Google Scholar 

  • White, D. A., 1973, The phospholipid composition of mammalian tissues, in: Function of Phospholipids (G. B. Ansell, J. N. Hawthorne, and R. M. Dawson, eds.), Elsevier, Amsterdam, pp. 441–482.

    Google Scholar 

  • Youdim, M. B. H., Ben-Schachar, D., and Riederer, P., 1993, The possible role of iron in the etiopathology of Parkinson’s disease, Movement Disorders 8:1–12.

    Article  PubMed  CAS  Google Scholar 

  • Zaleska, M. M., and Floyd, R. A., 1985, Regional lipid peroxidation in rat brain in vitro: Possible role of endogenous iron, Neurochem. Res. 10:397–410.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, J., and Piantodosi, C. A., 1994, Prolonged production of hydroxyl radical in rat hippocampus after brain ischemia-reperfusion is decreased by 21-aminosteroids, Neurosci. Letts. 177:127–130.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CNS Diseases Research, Pharmacia and Upjohn, Inc., Kalamazoo, Michigan, 49001, USA

    Edward D. Hall

Authors
  1. Edward D. Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Pennsylvania State University, Hershey, Pennsylvania, USA

    James R. Connor

Rights and permissions

Reprints and permissions

Copyright information

© 1997 Springer Science+Business Media New York

About this chapter

Cite this chapter

Hall, E.D. (1997). Antioxidant Therapeutic Strategies in CNS Disorders. In: Connor, J.R. (eds) Metals and Oxidative Damage in Neurological Disorders. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0197-2_17

Download citation

  • DOI: https://doi.org/10.1007/978-1-4899-0197-2_17

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4899-0199-6

  • Online ISBN: 978-1-4899-0197-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation